Abstract
Elevated proteasome activity extends lifespan in model organisms such as yeast, worms and flies. This pro-longevity effect might be mediated by improved protein homeostasis, as this protease is an integral module of the protein homeostasis network. Proteasomes also regulate cellular processes through temporal and spatial degradation of signaling pathway components. Here we demonstrate that the regulatory function of the proteasome plays an essential role in aging cells and that the beneficial impact of elevated proteasome capacity on lifespan partially originates from deregulation of the AMPK signaling pathway. Proteasome-mediated lifespan extension activity was carbon-source dependent and cells with enhancement proteasome function exhibited increased respiratory activity and oxidative stress response. These findings suggested that the pro-aging impact of proteasome upregulation might be related to changes in the metabolic state through a premature induction of respiration. Deletion of yeast AMPK, SNF1, or its activator SNF4 abrogated proteasome-mediated lifespan extension, supporting this hypothesis as the AMPK pathway regulates metabolism. We found that the premature induction of respiration in cells with increased proteasome activity originates from enhanced turnover of Mig1, an AMPK/Snf1 regulated transcriptional repressor that prevents the induction of genes required for respiration. Increasing proteasome activity also resulted in partial relocation of Mig1 from the nucleus to the mitochondria. Collectively, the results argue for a model in which elevated proteasome activity leads to the uncoupling of Snf1-mediated Mig1 regulation, resulting in a premature activation of respiration and thus the induction of a mitohormetic response, beneficial to lifespan. In addition, we observed incorrect Mig1 localization in two other long-lived yeast aging models: cells that overexpress SIR2 or deleted for the Mig1-regulator HXK2. Finally, compromised proteasome function blocks lifespan extension in both strains. Thus, our findings suggest that proteasomes, Sir2, Snf1 and Hxk2 form an interconnected aging network that controls metabolism through coordinated regulation of Mig1.
Highlights
Many genetic and pharmacological interventions that affect lifespan in model organisms modulate the respiratory capacity of the mitochondria and change the metabolic status of cells
We find that Mig1, a transcriptional repressor downstream of yeast AMPK, sucrose non-fermenting 1 kinase (Snf1), is a proteasome target and a negative regulator of lifespan
Our results uncover an interconnected network comprised of the proteasome, Sir2 and AMPK/Hxk2 signaling that impacts longevity through regulation of Mig1 and modulates respiratory metabolism
Summary
Many genetic and pharmacological interventions that affect lifespan in model organisms modulate the respiratory capacity of the mitochondria and change the metabolic status of cells. Several recent reports indicate that a moderate increase in ROS production in response to increased respiration activates a stress response that has a beneficial impact on lifespan [1, 4, 5, 6, 7]. This has given rise to the mitohormesis hypothesis, which posits that a low dose oxidative stress induced by increased respiratory activity has a beneficial impact on longevity
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